Tumor cytonemes, a new target for tumor suppression

肿瘤细胞因子，肿瘤抑制的新靶点

• 批准号: 9247168
• 负责人: THOMAS B. KORNBERG
• 金额: $ 20.68万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9247168
• 关键词: Adverse effects; Appearance; Attention; Cancer Model; Cell Communication; Cells; Cellular biology; Chemicals; Communication; Communities; Drosophila genus; EGF gene; Embryo; Engineering; Environment; Epithelial; Erinaceidae; Fibroblast Growth Factor; Filopodia; Goals; Growth Factor; Hereditary Disease; Homologous Gene; Image; Integral Membrane Protein; K-ras mouse model; Lead; Length; Limb structure; Link; Lung Adenocarcinoma; Malignant Neoplasms; Mediating; Membrane; Mesenchymal; Modality; Modeling; Mus; Neoplasm Metastasis; Normal Cell; Organ; Organelles; Paracrine Communication; Patients; Pharmaceutical Preparations; Play; Proteins; Radiation; Role; SHH gene; Signal Transduction; Signaling Protein; Stromal Cells; Structure; Synapses; System; Testing; Tissues; Toxin; Transforming Growth Factor alpha; Transforming Growth Factor beta; Tumor Biology; Tumor Cell Biology; Tumor Stem Cells; Tumor Suppression; Work; Zebrafish; base; cancer cell; cancer therapy; cell growth; density; mouse model; mutant; neoplastic cell; novel; public health relevance; receptor; response; smoothened signaling pathway; targeted treatment; therapeutic target; tumor; tumor growth; tumor microenvironment; tumor progression; tumorigenesis; uptake

 DESCRIPTION (provided by applicant): Recent progress in tumor biology has revealed that stromal cells - the non-transformed neighbors of tumor cells - play essential roles for tumor stem cells, tumor progression and metastasis. These roles involve communication between tumor and stromal cells, but the signals that are exchanged and the mechanism by which these signals move and elicit responses remain obscure. This is a proposal to build on our recent discovery that specialized organelles called cytonemes move and exchange signaling proteins between epithelial and mesenchymal cells in Drosophila - revealing that paracrine signaling in these normal contexts is mediated by cytonemes that make direct synaptic contacts between signaling cells. Importantly, we also identified mutant genetic conditions that compromised cytonemes and eliminated the contacts cytonemes normally make to mediate signaling, and showed that signaling was abrogated if cytonemes did not make direct synaptic contacts with target cells. All the paracrine signaling was cytoneme-dependent. We also tested the prediction that tumor cells communicate with stromal neighbors by a similar mechanism, and when we examined cells in a Drosophila tumor model, we detected cytonemes that extend from tumor cells to their normal neighbors. The presence of these organelles is consistent with the idea that they mediate signaling between tumor and stromal cells. The objective of the work proposed here is to investigate the role of cytonemes in tumorigenesis in Drosophila and mouse models. The goals are to identify where and in what form cytonemes are present, discover how cytonemes link tumor cells with their non-transformed neighbors, and determine whether cytoneme-mediated signaling is essential for the tumor growth. Based on previous studies, the likelihood that cytonemes are present and have essential roles in the vertebrate contexts is high. The proposed work may open a new avenue for controlling tumor growth, and by bringing this novel mechanism of cell-cell communication to the attention of the broader community of cancer biologists, it may alert them to the importance of cytoneme-mediated signaling and to the practicality of harnessing it for studies and therapy.

 描述（由申请人提供）：肿瘤生物学的最新进展表明，基质细胞-肿瘤细胞的非转化邻居-在肿瘤干细胞、肿瘤进展和转移中发挥重要作用。这些作用涉及肿瘤和基质细胞之间的通信，但交换的信号以及这些信号移动和引发反应的机制仍然不清楚。这是一个建立在我们最近发现的基础上的建议，即在果蝇的上皮细胞和间充质细胞之间移动和交换信号蛋白的专门细胞器称为cytonemes-揭示了在这些正常情况下的旁分泌信号是由cytonemes介导的，这些cytonemes在信号细胞之间进行直接突触接触。重要的是，我们还鉴定了损害细胞丝并消除细胞丝通常介导信号传导的接触的突变遗传条件，并表明如果细胞丝不与靶细胞直接突触接触，则信号传导被废除。所有的旁分泌信号都依赖于细胞丝。我们还测试了肿瘤细胞通过类似机制与基质邻居通信的预测，当我们检查果蝇肿瘤模型中的细胞时，我们检测到从肿瘤细胞延伸到正常邻居的细胞丝。这些细胞器的存在与它们介导肿瘤和基质细胞之间的信号传导的想法一致。本文的目的是研究果蝇和小鼠模型中细胞丝在肿瘤发生中的作用。目标是确定细胞丝在哪里以及以什么形式存在，发现细胞丝如何将肿瘤细胞与其未转化的邻居联系起来，并确定细胞丝介导的信号传导是否对肿瘤生长至关重要。基于先前的研究，细胞素存在的可能性很高，并在脊椎动物的背景下发挥重要作用。这项工作可能为控制肿瘤生长开辟了一条新的途径，通过将这种细胞间通讯的新机制引起更广泛的癌症生物学家的注意，它可能会提醒他们注意细胞丝介导的信号传导的重要性以及利用它进行研究和治疗的实用性。